Spinocerebellar ataxia type 14 (SCA14; Online Mendelian Inheritance in Man, OMIM #605361) is an autosomal dominant neurodegenerative disorder characterized by mild and slowly progressive cerebellar ataxia. Additional symptoms, including myoclonus, spasticity, dystonia, disturbance of deep sensation, and cognitive impairment, are observed in some patients [1, 2]. The SCA14 is caused by mutations in the protein kinase C gamma (PRKCG) gene (OMIM *176980), which encodes protein kinase C gamma (PKCc). PRKCG contains 18 exons, and the PKCc protein is composed of regulatory C1 and C2 domains and catalytic C3 and C4 domains. Most PRKCG mutations described till this date lie in the C1 domain [3, 4], while no mutations have been found in the C2 domain so far. Here we describe, for the first time, a mutation in the C2 domain in a patient with a typical SCA14 phenotype. A 58-year-old Japanese woman visited our hospital with gait disturbance and lisping, the latter being noticed by her husband. At the age of 40, she frequently experienced unsteadiness. At the age of 55, she visited a clinic after experiencing a fall, and brain imaging revealed cerebellar atrophy. Her father suffered from gait disturbance and dysphagia in his late 70s, and her father’s brother (the patient’s uncle) and his nephew (the patient’s cousin) had an unsteady gait. This family history indicated autosomal dominant inheritance (Fig. 1a). Neurological examination revealed cerebellar ataxia, including slurred speech, saccadic eye movement, and limb and truncal ataxia. Although there was a mild decrease in the deep sensations in her lower limbs, her gait disturbance was mostly consistent with ataxic gait. At her first visit to our institution, she had a score of 27/100 on the International Cooperative Ataxia Rating Scale. Blood, respiratory function, and cerebrospinal fluid tests yielded no remarkable findings. Brain magnetic resonance imaging demonstrated cerebellar atrophy, particularly in the upper part (Fig. 1b), and N-isopropyl-p-[123I]-iodoamphetamine single-photon emission computed tomography revealed decreased blood flow only in the upper cerebellum. She had no autonomic failure or cognitive dysfunction. Clinically, her symptoms corresponded with typical SCA14 features. While she had a family history of autosomal dominant inheritance, genetic testing for SCA types 1, 2, 3, 6, 7, 8, and 31 and dentatorubral–pallidoluysian atrophy, genes relatively frequent in Japan, did not show the presence of abnormal alleles. Next, to test for mutations in PRKCG, we performed genomic PCR followed by a direct sequencing analysis. This revealed the presence of the single-base substitution c.518T[G in exon five involving amino acid change p.Ile173Ser (Fig. 1c). This substitution has not been reported, either as a single-nucleotide polymorphism or as a mutation. The amino acid p.Ile173 residue is conserved among PRKCG proteins from mammals and zebrafish (Fig. 1d). To ascertain whether this was a disease-associated mutation, we first performed direct sequencing of this region in 200 Japanese healthy controls and found that none of them carried this alternative allele. Next, we employed three computer algorithms to predict the effect of this novel mutation: Sorting Intolerant From Tolerant (SIFT, http://sift.bii.a-star.edu.sg/), Polymorphism Phenotyping v2 T. Ueda (&) T. Seki K. Katanazaka K. Sekiguchi K. Kobayashi F. Kanda T. Toda Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-chou, Chuo-ku, Kobe 650-0017, Japan e-mail: taueda@med.kobe-u.ac.jp
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Nov 16, 2022
Robin Cabeza-Ruiz + 3
Open Access